| [Download PDF]
|Year : 2015 | Volume
| Issue : 2 | Page : 169--172
Approach to metabolic syndrome in childhood cancer survivors
JX Scott, MS Latha, R Aruna
Department of Pediatrics, Division of Pediatric Hemato Oncology, Sri Ramachandra University, Chennai, Tamil Nadu, India
J X Scott
Department of Pediatrics, Division of Pediatric Hemato Oncology, Sri Ramachandra University, Chennai, Tamil Nadu
The combined effects of optimized chemotherapy, surgery, radiotherapy, stem cell transplantation regimens, and improved supportive care had drastically increased the survival rate of childhood cancer. Hence, the number of adult survivors of childhood cancer is on the raise and this subset of population is gaining more attention due to the late effects of their cancer therapy. There is growing evidence that pediatric cancer survivors are at a greater risk of developing metabolic syndrome (MS) or the MS component traits than the general population. There is currently no drug therapy to treat MS as a whole disease, as it is a cluster of symptoms that present uniquely among different individuals. Given the recent recognition of MS in adult survivors of childhood cancer, there is a scarcity of long-term follow-up studies of this group. Adherence to a healthy lifestyle with both dietary and physical activity is the only most powerful and most useful armor available now against obesity and its metabolic complications.
|How to cite this article:|
Scott J X, Latha M S, Aruna R. Approach to metabolic syndrome in childhood cancer survivors.Indian J Cancer 2015;52:169-172
|How to cite this URL:|
Scott J X, Latha M S, Aruna R. Approach to metabolic syndrome in childhood cancer survivors. Indian J Cancer [serial online] 2015 [cited 2022 Aug 8 ];52:169-172
Available from: https://www.indianjcancer.com/text.asp?2015/52/2/169/175840
Modern, risk-based therapy with a multimodality approach to surgery, chemotherapy, radiotherapy, stem cell transplant and targeted regimens have led to 5 years survival rates of 80% in the childhood cancer survivors.,
As a result, the numbers of childhood cancer survivors who reach adulthood, and present with treatment-related health problems, have been on the rise. The incidence of cardiac problems, pulmonary complications, second malignancies, impaired fertility, osteoporosis, and obesity have been well documented in survivors of childhood cancer. Gonodal dysfunction, growth hormone (GH) deficiency, and hypothyroidism are the well-known endrocrine complications and of late, the increasingly recognized features are those of metabolic syndrome (MS)., Survivors of specific pediatric cancer groups such as central nervous system (CNS) tumors, lymphomas, sarcomas, neuroblastomas, acute lymphoblastic leukemia (ALL), Wilms tumors, testicular tumors, and post bone marrow transplant have been found to present with clinical features of MS and therefore are at increased risk of developing the risk factors of cardiovascular disease (CVD).,,,,,
As childhood cancer survivors have increased the risk of dyslipidemia, insulin resistance (IR), obesity and hypertension, American Heart Association and the Council for Cardiovascular Disease in the Young, have declared the post cancer treatment survivors as tier III, implicating that they are at increased risk of manifesting CVD early in adult life.,
Childhood cancer survivors have been found to have a cumulative incidence of coronary artery disease of 5.3% by the age of 45 years.
Although several childhood cancer survivor studies have shown the possible relationship between treatment and increased risk of developing risk factors for MS, many of these are limited by small sample sizes, and many studied only one or two features of the MS and focused on only one type of cancer. Hence, a review of literature using the keywords of MS, childhood cancer survivors, obesity, dyslipidemia, hypertension, IR was done in PubMed database.
MS is a term that encompasses a number of metabolic abnormalities including hyperinsulinemia, glucose intolerance, hypertension, obesity, IR and dyslipidemia. In 1988, Reaven noted that several risk factors for CVD commonly cluster together and he recognized them as a disease, syndrome X, currently known as MS. IR is considered the primary cause of associated cardiovascular risk factors and the probable mechanism linking all the MS comprising features.
Though clinical criteria for the diagnosis of MS in adults have been well emphasized, there are several difficulties in determining the MS features in the pediatric population. Insulin sensitivity, an important diagnostic condition for MS, is difficult to obtain in pediatric patients as insulin sensitivity changes with age and puberty and it is also negatively correlated with visceral obesity. Rather than body mass index (BMI), waist circumference specific to ethnic origin are being increasingly used in MS definition criteria in pediatric patients. The International Diabetes Federation has also redefined the MS in children and adolescents, recommending the required parameters in absolute values rather than age-related percentile cut-offs. MS should not be diagnosed in children younger than 10 years.
Ever since Reaven identified the syndrome X, there have been many definitions for MS through the years and the 2007 consensus group of the International Diabetes Foundation (IDF) uses a simple definition that can be employed in a clinical setting and is the most commonly used. IDF necessitates the BMI more than 90th percentile and two of the five defining criteria-waist circumference >90th percentile, blood pressure systolic >130 mmHg, and diastolic >85 mmHg, triglycerides >150 mg/dl, high-density lipoprotein cholesterol (HDL-C) <40 mg/dl, and fasting glucose >100 mg/dl.
The prevalence of MS in healthy children and adolescents ranges between 3.6% and 4.8%, but it increases dramatically up to 30–50% among overweight and obese children and adolescents., Due to the improved survival rates, more of the survivors of childhood cancer are now getting increased attention to identify the late effects of the therapy. A standardized mortality ratio of 9.7 for circulatory diseases has been found in survivors of childhood cancer. Trimis et al. studied the prevalence of MS in 80 survivors of ALL and found a twofold increased prevalence in those treated with chemotherapy alone and a fivefold increase in those treated with chemotherapy and radiotherapy. Hoffman et al. assessed the MS in sarcoma survivors and identified an increased prevalence among those aged 20–39 years. He found that in male survivors, testosterone levels declined as the number of MS traits increased, thereby indicating the relationship between gonadal function and MS. In a group of 466 adult childhood cancer survivors, Van Waas et al. assessed the MS as per modified national cholesterol education program (NCEP) criteria and found a prevalence of 12.6%. Taskinen et al. determined the MS among long-term survivors of bone marrow transplant and identified a prevalence of 38%. MS was found in 60% of patients with GH deficiency in contrast to only 19% of patients with normal GH levels.
Insulin resistance and dyslipidemia
In childhood cancer survivors, the cancer therapies have been found to activate certain pathways that lead to hormone deficiencies, changes in insulin sensitivity, lipid metabolism, inflammatory mediators, and adipokines. Chemotherapy causes damage to endocrine organs, magnesium metabolism and adipose tissue and endothelial dysfunction thereby leading to increased cardiovascular risk., Combination of chemotherapy and radiation depletes osteoblast and estrogenic precursors, leading to a significant decrease in plasma osteocalcin levels, thereby contributing to impaired glucose tolerance. Chemotherapy and glucocorticoids impair skeletal muscle glucose uptake and transport, predisposing to inflammation and atherogenic dyslipidemia by producing reactive oxygen species and stimulating hepatic de novo lipogenesis. Chemotherapy causes a direct damage to the functional integrity of the endothelium and disrupts nitric oxide pathway.,,,,
It is the viscerally distributed adipose tissue rather than subcutaneous fat that plays a significant role in MS. Adipose tissue, considered as an endocrine organ secretes inflammatory mediators and adipokines that regulate endothelial function, atherogenesis, and energetic balance. Systemic inflammation related to cancer itself and amplified by treatment creates the primary damage of adipose tissue resulting in adipocyte dysfunction and decreased adiponectin secretion. Adipokines also activate intracellular pathways regulating the subacute inflammatory state associated with obesity and development of IR and Type 2 diabetes mellitus. The more the components of MS that are evident, higher is the cardiovascular mortality rate., A substantial proportion of adult survivors of childhood ALL has been found to have abdominal aortic calcification, which is a marker of early atherosclerotic disease and MS.,
GH deficiency in childhood cancer survivors may be due to the CNS tumor location itself or as an adverse effect of cranial radiotherapy and chemotherapy. GH deficiency frequently induces MS like disorders, such as hypertriglyceridemia, low HDL-C, coagulopathy, and hypertension. The two important conditions related to GH deficiency are IR and endothelial dysfunction.
Estrogens and testosterone are known to influence body composition, lipid metabolism, vascular tone, and blood pressure. Gonadal failure is a frequent adverse effect in long-term cancer survivors, which may result in impaired hormonal production and the risk of developing MS. Chemotherapy comprising alkylant agents and platinum compounds may cause gonadal failure. Magnesium plays a role in insulin sensitivity and vascular tone. Hypomagnesemia has been implicated in the development of IR, hypertension, increasing the risk of atherosclerosis and CVD. Cisplatin-containing cytotoxic agents are the common drugs causing hypomagnesemia.
Tumors of CNS requiring craniospinal radiotherapy, lymphomas, neck tumors, conditioning total body irradiation are the causes of thyroid dysfunction. The hypothyroid state affects the cardiovascular system through both an influence on the heart and adverse effects on serum lipids, increasing the risk of development of CVD. Hypothyroidism causes modest weight gain, due to fluid retention and decreased metabolism. Decreased thyroid hormone can increase levels of total cholesterol and a change in HDL-C due to alteration in metabolic clearance. Hypothyroidism also causes fatigue, loss of energy, contributing to weight gain.
Excessive weight gain during ALL treatment is usually related to steroids effects, CNS treatment on appetite regulation and as well as less energy expenditure. The association of obesity and cranial radiotherapy is well established and the cancer survivors who received >20 Gy cranial RT were at increased risk of overweight and obesity especially females who were treated at a young age (<5 years). Variation of long-term toxicity in equally treated subjects, suggests that genetic and environmental factors influence the incidence and severity of late effects. The development of a secondary leptin resistance plays a role in the onset and progression of obesity in ALL survivors, which was evident in people treated with cranial radiotherapy. Overweight and obese female survivors were found to be more frequently homozygous for a polymorphism of the leptinreceptor, associated with obesity in the general population., An adiposity rebound early after the completion of therapy has been described in childhood ALL survivors, which could explain the increased obesity risk in patients treated at a very young age.
The premature atherosclerotic changes in the arterial wall, following radiotherapy, has been found to be responsible for the increased risk of developing stroke in Hodgkins disease, brain tumors and ALL.,
Treatment of CNS tumors commonly leads to obesity and multiple pituitary hormone deficiencies. Long-term survivors of childhood CNS tumors who had received cranial radiotherapy exceeding 45 Gy have been found to have elevated systolic blood pressure, altered body composition, altered lipid profile making them prone for CVD by Heikens et al. The hypothalamic and pituitary irradiation causes disruption of the appetite-regulating center causing hyperphagia and consequently progressive obesity. Pituitary irradiation may also cause GH deficiency and central hypogonadism. These conditions determine an IR state, contributing to the development of MS and diabetes mellitus. Irradiation and chemotherapy could also cause direct damage on the pancreatic beta cells leading to impairment of insulin secretion.
Many childhood cancer survivors are less physically active than their peers. A Canadian study has found that only half of childhood cancer survivors met public health physical activity guidelines. Long-term survivors of childhood ALL were less likely to meet physical activity recommendations and more likely to report no leisure-time physical activity than controls. They have been shown to have lower exercise capacity than their siblings.
The major recommendations for the childhood cancer survivors by Kavey et al. focuses on six major aspects namely, strict adherence to age appropriate reduced calorie training, to maintain a normal blood pressure, serum lipid and blood glucose levels, strong anti-smoking counseling, and to encourage physical activity.
Primary prevention involves prevention of hormonal deficiencies, direct endothelial damage, chemotherapy dose reduction, avoidance of unnecessary gonadotoxic chemotherapy, and administration of alternative drugs. Secondary prevention should include the supplementation of hormonal deficiencies, treatment of therapy-related endothelial dysfunction like IR, dyslipidemia and magnesium supplementation and screening for occurrence of MS and treatment when appropriate.
Hypothalamic obesity often results in devastating metabolic and psychosocial complications, requiring the provision of dietary and behavioral modifications, encouragement of regular physical activity and psychological counseling.
The primary approach to the prevention and treatment of MS is lifestyle modification. While a substantial component of MS is attributed to unhealthy diet and sedentary lifestyle, following a healthy diet and maintaining a normal physical activity would be of utmost significance in preventing them.
Adherence to a heart healthy lifestyle which involved both dietary and physical activity guidelines has been found to lower the risk of MS among childhood cancer survivors. Slater et al. state that higher levels of physical activity can address the serious long-term consequences of MS in childhood cancer survivors and is an important strategy to maintain good health in these vulnerable population.,,, Regular monitoring of blood pressure and hypertension control are important measures to prevent cardiovascular disease, as is smoking cessation. Replacement therapy for GH is also a part of the management of MS.,
With the better care committed to children with cancer, the survival rates are greatly improving, and MS is becoming the major target for intervention in the follow-up of cancer survivors. Hence, it is pertinent that physicians providing primary care to these adult survivors should be aware of the adverse effects of the long-term hormonal deficiencies and cardiovascular and diabetes risk profiles, following cancer treatment. As dyslipidemia and hypertension are often asymptomatic, screening is important in the follow-up. As MS cannot be treated by a single drug therapy, the individual risk factors should be treated separately.
One of the effective and practical solutions to address MS in clinical practice is to have a regular discussion about health-promoting behaviors between the health care providers and childhood cancer survivors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Surveillance, Epidemiology, and End Results Program, 1975-2003, Div. of Cancer Control and Pop. Sciences, NCI; 2006.|
|2||Gurney J, Bondy M. Epidemiology of childhood cancer. In: Pizzo PA, Poplack DG, editors. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia: Lippincott Williams and Wilkins; 2006. p. 1-13.|
|3||Robison LL, Green DM, Hudson M, Meadows AT, Mertens AC, Packer RJ, et al. Long-term outcomes of adult survivors of childhood cancer. Cancer 2005;104 11 Suppl: 2557-64.|
|4||Diller L, Chow EJ, Gurney JG, Hudson MM, Kadin-Lottick NS, Kawashima TI, et al. Chronic disease in the childhood cancer survivor study cohort: A review of published findings. J Clin Oncol 2009;27:2339-55.|
|5||Chemaitilly W, Sklar CA. Endocrine complications in long-term survivors of childhood cancers. Endocr Relat Cancer 2010;17:R141-59.|
|6||Link K, Moëll C, Garwicz S, Cavallin-Ståhl E, Björk J, Thilén U, et al. Growth hormone deficiency predicts cardiovascular risk in young adults treated for acute lymphoblastic leukemia in childhood. J Clin Endocrinol Metab 2004;89:5003-12.|
|7||Nuver J, Smit AJ, Wolffenbuttel BH, Sluiter WJ, Hoekstra HJ, Sleijfer DT, et al. The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol 2005 23:3718-25.|
|8||Gurney JG, Ness KK, Sibley SD, O'Leary M, Dengel DR, Lee JM, et al. Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia. Cancer 2006;107:1303-12.|
|9||Neville KA, Cohn RJ, Steinbeck KS, Johnston K, Walker JL. Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: Prevalence and risk factors. J Clin Endocrinol Metab 2006;91:4401-7.|
|10||Taskinen M, Lipsanen-Nyman M, Tiitinen A, Hovi L, Saarinen-Pihkala UM. Insufficient growth hormone secretion is associated with metabolic syndrome after allogeneic stem cell transplantation in childhood. J Pediatr Hematol Oncol 2007;29:529-34.|
|11||Hoffman KE, Derdak J, Bernstein D, Reynolds JC, Avila NA, Gerber L, et al. Metabolic syndrome traits in long-term survivors of pediatric sarcoma. Pediatr Blood Cancer 2008;50:341-6.|
|12||Oeffinger KC, Buchanan GR, Eshelman DA, Denke MA, Andrews TC, Germak JA, et al. Cardiovascular risk factors in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2001;23:424-30.|
|13||Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, et al. Cardiovascular risk reduction in high-risk pediatric patients: A scientific statement from the American Heart Association expert panel on population and prevention science; the councils on cardiovascular disease in the young, epidemiology and prevention, nutrition, physical activity and metabolism, high blood pressure research, cardiovascular nursing, and the kidney in heart disease; and the interdisciplinary working group on quality of care and outcomes research: Endorsed by the American Academy of Pediatrics. Circulation 2006;114:2710-38.|
|14||Armstrong GT, Oeffinger KC, Chen Y, Kawashima T, Yasui Y, Leisenring W, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 2013;31:3673-80.|
|15||Talvensaari KK, Lanning M, Tapanainen P, Knip M. Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome. J Clin Endocrinol Metab 1996;81:3051-5.|
|16||Sarti C, Gallagher J. The metabolic syndrome: Prevalence, CHD risk, and treatment. J Diabetes Complications 2006;20:121-32.|
|17||Zimmet P, Alberti G, Kaufman F, Tajima N, Silink M, Arslanian S, et al. The metabolic syndrome in children and adolescents. Lancet 2007;369:2059-61.|
|18||Bizzarri C, Bottaro G, Pinto RM, Cappa M. Metabolic syndrome and diabetes mellitus in childhood cancer survivors. Pediatr Endocrinol Rev 2014;11:365-73.|
|19||Levy-Marchal C, Arslanian S, Cutfield W, Sinaiko A, Druet C, Marcovecchio ML, et al. Insulin resistance in children: Consensus, perspective, and future directions. J Clin Endocrinol Metab 2010;95:5189-98.|
|20||MacArthur AC, Spinelli JJ, Rogers PC, Goddard KJ, Abanto ZU, McBride ML. Mortality among 5-year survivors of cancer diagnosed during childhood or adolescence in British Columbia, Canada. Pediatr Blood Cancer 2007;48:460-7.|
|21||Trimis G, Moschovi M, Papassotiriou I, Chrousos G, Tzortzatou-Stathopoulou F. Early indicators of dysmetabolic syndrome in young survivors of acute lymphoblastic leukemia in childhood as a target for preventing disease. J Pediatr Hematol Oncol 2007;29:309-14.|
|22||van Waas M, Neggers SJ, Pieters R, van den Heuvel-Eibrink MM. Components of the metabolic syndrome in 500 adult long-term survivors of childhood cancer. Ann Oncol 2010;21:1121-6.|
|23||Nuver J, Smit AJ, Postma A, Sleijfer DT, Gietema JA. The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures. Cancer Treat Rev 2002;28:195-214.|
|24||Davies JH, Evans BA, Jenney ME, Gregory JW.In vitro effects of combination chemotherapy on osteoblasts: Implications for osteopenia in childhood malignancy. Bone 2002;31:319-26.|
|25||Han B, Yang Z, Nimni M. Effects of gamma irradiation on osteoinduction associated with demineralized bone matrix. J Orthop Res 2008;26:75-82.|
|26||Jornayvaz FR, Samuel VT, Shulman GI. The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. Annu Rev Nutr 2010;30:273-90.|
|27||Stump CS, Henriksen EJ, Wei Y, Sowers JR. The metabolic syndrome: Role of skeletal muscle metabolism. Ann Med 2006;38:389-402.|
|28||Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathophysiological mechanisms. Circulation 2006;113:1888-904.|
|29||Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K; DECODE Study Group. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 2004;164:1066-76.|
|30||Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793-801.|
|31||Gurney JG, Ojha RP, Ness KK, Huang S, Sharma S, Robison LL, et al. Abdominal aortic calcification in young adult survivors of childhood acute lymphoblastic leukemia: Results from the St. Jude Lifetime Cohort study. Pediatr Blood Cancer 2012;59:1307-9.|
|32||Chaosuwannakit N, D'Agostino R Jr., Hamilton CA, Lane KS, Ntim WO, Lawrence J, et al. Aortic stiffness increases upon receipt of anthracycline chemotherapy. J Clin Oncol 2010;28:166-72.|
|33||Gleeson HK, Shalet SM. The impact of cancer therapy on the endocrine system in survivors of childhood brain tumours. Endocr Relat Cancer 2004;11:589-602.|
|34||Oeffinger KC, Mertens AC, Sklar CA, Yasui Y, Fears T, Stovall M, et al. Obesity in adult survivors of childhood acute lymphoblastic leukemia: A report from the childhood cancer survivor study. J Clin Oncol 2003;21:1359-65.|
|35||Siviero-Miachon AA, Spinola-Castro AM, Tosta-Hernandez PD, de Martino Lee ML, Petrilli AS. Leptin assessment in acute lymphocytic leukemia survivors: Role of cranial radiotherapy? J Pediatr Hematol Oncol 2007;29:776-82.|
|36||Ross JA, Oeffinger KC, Davies SM, Mertens AC, Langer EK, Kiffmeyer WR, et al. Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: A report from the childhood cancer survivor study. J Clin Oncol 2004;22:3558-62.|
|37||Reilly JJ, Kelly A, Ness P, Dorosty AR, Wallace WH, Gibson BE, et al. Premature adiposity rebound in children treated for acute lymphoblastic leukemia. J Clin Endocrinol Metab 2001;86:2775-8.|
|38||Bowers DC, McNeil DE, Liu Y, Yasui Y, Stovall M, Gurney JG, et al. Stroke as a late treatment effect of Hodgkin's Disease: A report from the childhood cancer survivor study. J Clin Oncol 2005;23:6508-15.|
|39||Bowers DC, Liu Y, Leisenring W, McNeil E, Stovall M, Gurney JG, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: A report from the Childhood Cancer Survivor Study. J Clin Oncol 2006;24:5277-82.|
|40||Heikens J, Ubbink MC, van der Pal HP, Bakker PJ, Fliers E, Smilde TJ, et al. Long term survivors of childhood brain cancer have an increased risk for cardiovascular disease. Cancer 2000;88:2116-21.|
|41||Hoffman MC, Mulrooney DA, Steinberger J, Lee J, Baker KS, Ness KK. Deficits in physical function among young childhood cancer survivors. J Clin Oncol 2013;31:2799-805.|
|42||Smith WA, Li C, Nottage KA, Mulrooney DA, Armstrong GT, Lanctot JQ, et al. Lifestyle and metabolic syndrome in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort study. Cancer 2014;120:2742-50.|
|43||Slater ME, Ross JA, Kelly AS, Dengel DR, Hodges JS, Sinaiko AR, et al. Physical activity and cardiovascular risk factors in childhood cancer survivors. Pediatr Blood Cancer 2014;62:305-10.|
|44||Speck RM, Courneya KS, Mâsse LC, Duval S, Schmitz KH. An update of controlled physical activity trials in cancer survivors: A systematic review and meta-analysis. J Cancer Surviv 2010;4:87-100.|
|45||Stolley MR, Restrepo J, Sharp LK. Diet and physical activity in childhood cancer survivors: A review of the literature. Ann Behav Med 2010;39:232-49.|
|46||Ballard-Barbash R, Friedenreich CM, Courneya KS, Siddiqi SM, McTiernan A, Alfano CM. Physical activity, biomarkers, and disease outcomes in cancer survivors: A systematic review. J Natl Cancer Inst 2012;104:815-40.|
|47||Miller TL, Lipsitz SR, Lopez-Mitnik G, Hinkle AS, Constine LS, Adams MJ, et al. Characteristics and determinants of adiposity in pediatric cancer survivors. Cancer Epidemiol Biomarkers Prev 2010;19:2013-22.|